Walter Fries

Advanced Age Is an Independent Risk Factor for Severe Infections and Mortality in Patients Given Anti–Tumor Necrosis Factor Therapy for Inflammatory Bowel Disease

BACKGROUND & AIMS Few data are available on effects of biologic therapies in patients more than 65 years old with inflammatory bowel disease (IBD). We evaluated the risk and benefits of therapy with tumor necrosis factor (TNF) inhibitors in these patients. METHODS We collected data from patients with IBD treated with infliximab (n = 2475) and adalimumab (n = 604) from 2000 to 2009 at 16 tertiary centers. Ninety-five patients (3%) were more than 65 years old (52 men; 37 with ulcerative colitis and 58 with Crohns disease; 78 treated with infliximab and 17 with adalimumab). The control group comprised 190 patients 65 years old or younger who were treated with both biologics and 190 patients older than 65 years who were treated with other drugs. The primary end points were severe infection, cancer, or death. RESULTS Among patients more than 65 years old who received infliximab and adalimumab, 11% developed severe infections, 3% developed neoplasms, and 10% died. No variable was associated with severe infection or death. Among control patients more than 65 years old, 0.5% developed severe infections, 2% developed cancer, and 2% died. Among control patients less than 65 years old, 2.6% developed severe infections, none developed tumors, and 1% died. CONCLUSIONS Patients older than 65 years treated with TNF inhibitors for IBD have a high rate of severe infections and mortality compared with younger patients or patients of the same age that did not receive these therapeutics. The effects of anti-TNF agents in older patients with IBD should be more thoroughly investigated, because these patients have higher mortality related to hospitalization than younger patients.

Calprotectin and lactoferrin in the assessment of intestinal inflammation and organic disease

Background and aimsCalprotectin and lactoferrin are specific neutrophil-derived proteins, which can be measured in the feces because they are released by cells in inflammatory conditions. We evaluated the efficacy of calprotectin and lactoferrin in detecting organic disease as assessed by colonoscopy.MethodsThe study comprised 144 patients undergoing colonoscopy for lower gastrointestinal symptoms (abdominal pain, altered bowel habits, and bloody stools) (67), or inflammatory bowel disease activity, or surveillance for dysplasia (77). A single stool sample was assayed for calprotectin and lactoferrin. The proportion of patients correctly diagnosed with each test and the relationship with endoscopic and histological findings were measured.ResultsFecal excretion of calprotectin significantly correlated with the finding of colonic inflammation at endoscopy, both in ulcerative colitis and in Crohn’s disease (p<0,001 and p<0,008, respectively), while lactoferrin excretion significantly correlated with histological inflammation (p=0.001 and p=0.009 respectively). Recommended cut-off values need to be adjusted in the inflammatory bowel disease group. Overall sensitivity, specificity, positive predictive value, and diagnostic efficacy were 78, 83, 86, and 80% for calprotectin and 80, 85, 87, and 81% for lactoferrin, respectively.ConclusionsFecal calprotectin and lactoferrin appear to be equally recommendable as inflammatory disease markers in patients with lower gastrointestinal symptoms. Both tests are needed to accurately discriminate activity in inflammatory bowel disease patients.

Prospective comparison of computed tomography enterography and magnetic resonance enterography for assessment of disease activity and complications in ileocolonic Crohn's disease

Background: Studies comparing magnetic resonance enterography (MRE) and computerized tomography enterography (CTE) for Crohns disease (CD) are scarce. Methods: The aim of this study was to prospectively compare the sensitivity, specificity, and accuracy of abdominal MRE and CTE to assess disease activity and complications (fistulas, strictures) in ileocolonic CD. A total of 44 patients (23 male; 21 female; mean age 44) with ileocolonic CD underwent both MR and CT in a short time interval (mean 5 days). A 16‐slice CT with intravenous contrast and an MRI with oral and paramagnetic intravenous contrast were performed. Ileocolonoscopy was used as the reference standard. Sensitivity values of CT and MR for detection of extraenteric signs of disease were compared with the McNemar test, with results of imaging studies, surgery, and physical examination as reference standards. Results: No significant differences in sensitivity, specificity, and accuracy were observed between MRE and CTE regarding the following parameters at the patient level: localization of CD (P = 1.0), bowel wall thickening (P = 1.0), bowel wall enhancement (P = 1.0), enteroenteric fistulas (P = 0.08), detection of abdominal nodes (P = 1.0), and perivisceral fat enhancement (P = 0.31). MR was significantly superior compared to CT in detecting strictures (P = 0.04). Per segment analysis showed that MRE was significantly superior to CTE in detecting ileal wall enhancement (P = 0.02). Conclusions: MR and CT are equally accurate to assess disease activity and bowel damage in CD. MR may be superior to CT in detecting intestinal strictures and ileal wall enhancement. MR may represent an alternative technique to CT in assessing ileocolonic CD. (Inflamm Bowel Dis 2010)

Hepatitis B and C Virus Infection in Crohn's Disease

Patients with Crohns disease (CD) are at higher risk of hepatitis C (HCV) and B virus (HBV) infection, because of surgical and/or endoscopic procedures. However, the prevalence of HCV and HBV infection in CD is unknown. This issue may be relevant because of the growing use of immunomodulatory drugs in CD. The purpose of this study was to assess, in a multicenter study, the prevalence and risk factors of HCV and HBV infection in CD. The effect of immunomodulatory drugs for CD on the clinical course of hepatitis virus infections and of interferon-&agr; (IFN-&agr;) on the course of CD was examined in a small number of patients. Sera from 332 patients with CD and 374 control subjects (C) were tested for the following: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), HBcAb, HBeAg, HBeAb, anti-HCV, and HCV-RNA. An additional 162 patients with ulcerative colitis (UC) were tested as a disease control group. Risk factors were assessed by multivariate statistical analysis. Infection by either HCV or HBV was detected in 24.7% of patients with CD. In the age groups younger than 50 years, HCV prevalence was higher in CD than in C (p = 0.01). HCV infection in CD was associated with surgery (OR 1.71; 95% CI 1.00–2.93; p = 0.04), blood transfusions (OR 3.39; 95% CI 1.04–11.04; p = 0.04), and age (OR 2.3; 95% CI 1.61–3.56; p < 0.001). The event CD-related surgery appeared to be the main risk factor for HCV infection in CD. HCV prevalence was higher in CD (7.4%) than in UC (0.6%) (p = 0.001). HBcAb positivity was higher in CD (10.9%) and UC (11.5%) than in C (5.1%) (CD vs. C: p = 0.016; UC vs. C: p = 0.02), associated with age (OR 2.08; 95% CI 1.37–3.17; p = 0.001) and female gender (OR 2.68; 95% CI 1.37–3.17; p = 0.001) in CD and to UC duration (OR 1.20; 95% CI 1.06–1.36; p = 0.002). Immunomodulatory drugs did not influence the course of HBV or HCV infection in seven patients with CD, and IFN-&agr; for chronic hepatitis C did not affect CD activity in six patients with CD. It is concluded that HBV prevalence is higher in CD than in C at all ages, whereas HCV prevalence is increased in young patients with CD, because of a greater need for surgery. The higher HCV (but not HBV) prevalence in CD than in UC suggests that the host immune response may influence the risk of HCV infection. Although a relatively high proportion of patients with CD showed HBV and/or HCV infections, this should not influence treatment strategies for CD.

Treatment of acute uveitis associated with Crohn's disease and sacroileitis with infliximab.

asymptomatic controls. We obtained serum for qualitative H. pylori IgG from 16 patients who were diagnosed with either lymphocytic (n 9) or collagenous (n 7) colitis between January, 1995 and June, 2000. Identical testing was performed in 16 healthy, asymptomatic controls undergoing screening colonoscopy. Random colonic biopsies were obtained from each control patient to exclude microscopic colitis. Seroprevalence rates did not differ between both groups (50% in each). Seroprevalence was higher in the collagenous colitis subgroup when compared to controls (71% vs 50%), but the difference was not statistically significant. We concluded that patients with microscopic colitis were no more likely to be infected with H. pylori than controls, although the small number of patients was an obvious limitation of our study. Discovery of a consistently effective treatment for microscopic colitis has been hampered by the lack of a defined etiology for the disease. Speculation surrounding exposure of the colon to an unidentified infectious organism or luminal toxin is supported by a study that reported reversal of histological abnormalities in several patients with microscopic colitis after fecal stream diversion (3). Further support for an infectious etiology stems from reports of evolution of microscopic colitis after acute Campylobacter jejuni infection and persistent Clostridium difficile colitis (4, 5). Empirical therapy using single antibiotic regimens such as metronidazole or erythromycin, however, has only been reported anecdotally, and the response to these drugs is short lived (6, 7). Many regard bismuth subsalicylate as first-line therapy for microscopic colitis based on controlled data, and it too has known antimicrobial properties against enteric bacteria (8, 9). Response to combination antibiotic regimens like those used for treatment of H. pylori has not previously been reported, though. Although it is highly unlikely that H. pylori contributes to the development of microscopic colitis, it is plausible that an unidentified organism—one that is equally difficult to eradicate—may play a causative role. The duration of remission observed in our patients suggests that combination antimicrobial therapy may afford a more lasting effect. Raj I. Narayani, M.D., U.S.A.F.M.C. Mark P. Burton, M.D., U.S.A.F.M.C. Gavin S. Young, M.D., U.S.A.F.M.C. Wilford Hall United States Air Force Medical Center San Antonio, Texas

Intestinal permeability and genetic determinants in patients, first-degree relatives, and controls in a high-incidence area of Crohn's disease in Southern Italy.

OBJECTIVE:A defect of gastrointestinal barrier function is considered to represent an important step in the pathogenesis of Crohns disease (CD) but the mechanisms leading to an increased intestinal permeability (IP) are poorly understood. Since IP is influenced by pro-inflammatory mediators, it seems likely that a genetically determined abnormal immune response may lead to a loss of barrier function.METHODS:In a geographic area in Southern Italy with high incidence of CD we investigated IP (lactulose/mannitol testing) together with the three main mutations of the NOD2/CARD15 and the D299G polymorphism of the toll-like receptor (TLR)-4 gene in 23 families of CD patients (patients and first-degree relatives).RESULTS:Forty-eight percent of CD patients and 40% of their healthy relatives were found to have an abnormal IP compared to 5% of an appropriate control population (p < 0.0001). IP, however, was not associated with the L1007finsC mutation of the NOD2/CARD15 or the D299G variant of the TLR-4 gene. Allele frequency of the only L1007finsC mutation of CARD15 was significantly increased in patients (8.7%, p < 0.003) and in relatives (8.3%, p < 0.024) compared with controls (2.4%), whereas the D299G variant of the TLR-4 gene was found to be increased only in relatives (8.3%, p < 0.022), but not in patients (4.3%) compared with the control population (1.7%).CONCLUSIONS:There was no association between IP and genetic markers. Our findings showed a very high proportion of healthy first-degree relatives to bare alterations suggested to constitute determinants of CD. Mutations of NOD2/CARD15 or TLR-4, however, do not lead to permeability defects emphasizing the importance of additional environmental and/or genetic factors for pathogenesis.

Effects of immunosuppression on immune response to pneumococcal vaccine in inflammatory bowel disease: a prospective study.

Background: Since immunomodulators and antitumor necrosis factor (TNF) agents are increasingly used to treat inflammatory bowel disease (IBD), it is recommended to administer antipneumococcal vaccination to prevent opportunistic pneumonia. There is some evidence that concomitant immunosuppression may impair the immune response to vaccination. We aimed to evaluate the response rates to pneumococcal vaccination in four different treatment groups (mesalamine, azathioprine, infliximab, infliximab plus azathioprine). Methods: In all, 96 patients with IBD (54 with Crohns disease; 42 with ulcerative colitis) were administered a 23‐valent polysaccharide pneumococcal vaccine (PSV‐23). The levels of antipneumococcal antibodies were measured prior to and at least 3 weeks after vaccination. Response rates and risk factors for impaired immunosuppression were investigated. Patients on mesalamine were used as a control group. Results: Patients administered infliximab or the combination immunosuppressive therapy had significantly lower response rates to vaccination (57.6% and 62.5%, respectively) compared with the group on mesalamine (88.6%; P < 0.05 for both comparisons). Azathioprine alone did not influence the response rate to vaccination (78.9%; P = 0.43 vs. mesalamine group). Mean antibody titers after vaccination were significantly lower in patients under infliximab or combined immunosuppression than controls (P < 0.05). Immunosuppression with infliximab or combination therapy significantly decreased the likelihood of responding to vaccination (odds ratio [OR] = 0.17, 95% confidence interval [CI] 0.04–0.64, P = 0.009, and OR = 0.21, 95% CI 0.05–0.91, P = 0.038, respectively). Pneumococcal vaccination was generally safe and well tolerated. Conclusions: Anti‐TNF therapy alone or in combination with azathioprine impairs the response to pneumococcal vaccination in patients with IBD. All patients with IBD should therefore be vaccinated before starting anti‐TNF therapy. (Inflamm Bowel Dis 2012;)

Effect of stress on the paracellular barrier in the rat ileum

Background: Restraint stress induces permeability changes in the rat small intestine but little is known of the ultrastructural events leading to defects of the paracellular sealing or of the short term evolution of these alterations. Methods: In the present study, we performed transmission electron microscopy in the terminal ileum perfused with lanthanum after two hours of immobilisation stress and in non-stressed control rats. Moreover, immunohistochemistry of the tight junction (TJ) associated proteins, occludin and zonula occludens 1 (ZO-1), was carried out together with western blot analysis of the transmembrane protein occludin. TJ morphology was also assessed after a 22 hour recovery period. Results: Immobilisation stress induced a significant increase in epithelial permeability to the lanthanum tracer (p<0.005) which recovered completely after 22 hours. Compared with unstressed controls, in stressed rats no differences were found on freeze fracture analysis. The TJ related immunofluorescence signals of occludin and of ZO-1 were irregularly distributed in stressed rats after two hours but returned to a normal pattern at 24 hours although with minor intensity. No quantitative alterations in occludin were detectable in stressed rats by immunoblot whereas a perinuclear concentration of occludin was observed by immunolocalisation. Conclusions: Immobilisation stress induced an increase in TJ permeability in the rat terminal ileum. These changes were mainly due to modifications and redistribution of the TJ transmembrane protein occludin and of the plaque protein ZO-1 whereas protein synthesis, at least that of occludin, was not affected by stress.

Mucosal immunology and probiotics.

The cross-talk between the mucosa-associated immune system and microbiota is critical in mucosal tissue homeostasis as well as in protection against infectious and inflammatory diseases occurring at mucosal sites. This recent evidence has paved the way to therapeutic approaches aimed at modulating the mucosa-associated immune system using probiotics. Different strains of probiotics possess the ability to finely regulate dendritic cell (DC) activation, polarizing the subsequent T cell activity toward Th1 (e.g. Lactobacillus (Lb) acidophilus), Th2 (Lb.reuteri and Bifidobacterium bifidum) or, as more recently demonstrated, Th17 responses induced by specific strains such as Lb.rhamnosus GG and Lac23a, the latter isolated in our laboratory. Here, we review some recent advances in our understanding of probiotics effects on mucosal immunology, particularly on cells of the innate immunity such as DCs. We also highlight our own experiences in modulating DC functions by commensal bacteria and discuss the relevance of probiotics administration in the treatment of human immunopathologies.

Dynamics of enterocyte tight junctions: effect of experimental colitis and two different anti-TNF strategies

An alteration of the intestinal barrier is considered to represent an early step in pathogenesis of Crohns disease. The integrity of intestinal barrier function is guaranteed among other factors by enterocyte tight junction (TJ) proteins. Clinical and experimental data indicate the TNF-alpha to be the major responsible factor for these defects. In the present study we investigated the very early effects of DNBS-ethanol colitis on ileal enterocyte TJ proteins [occludin, zonula occludens-1 (ZO-1), claudin-2] in controls, mice treated with infliximab (IFX) or with etanercept (ETC), and in knockout mice for the TNF-alpha receptor 1 (TNFR-1(-/-)). Circulating TNF-alpha levels were effectively reduced by IFX and ETC (P < 0.01, both) at 3 and at 6 h. DNBS colitis induced disappearance of occludin and ZO-1 from enterocyte cell-cell contact, whereas claudin-2, absent under control conditions, appeared in the ileal epithelium. These alterations were prevented equally by both treatments, IFX and ETC, and in TNFR-1(-/-) animals. DNBS colitis induced a very rapid loss of occludin and ZO-1 from ileal TJ together with an upregulation of claudin-2. Our data are consistent with the hypothesis that TNF-alpha is involved in early TJ rearrangement and that its effects are mediated through TNFR-1. Despite clinical differences, both anti-TNF treatments were equally effective in the present setting.